Field of the Invention
The present invention relates to the prognosis of the progression of breast cancer in a patient, and more particularly to the prediction of the occurrence of metastasis in one or more tissue or organ of patients affected with a breast cancer. In particular embodiments, methods are provided for drug repositioning in patients with breast cancer brain metastasis, and for improving patient outcomes. Compositions and diagnostic kits for determining the likelihood of brain metastasis of breast cancer are also provided.
Description of Related Art
Central nervous system (CNS) metastases is the most common type of brain malignancy, and breast cancer is the second most common type of malignancy to cause CNS metastases. The incidence of brain metastases in breast cancer has been reported up to 26-48% in clinical series, and it is expected to continue to rise as we achieve better systemic control of the disease. Brain metastases are associated with poor patient survival and poor quality of life.
Breast cancer is the most common malignant disease among Western women. Unfortunately, it is not the primary tumor, but the occurrence of metastases in distant organs that is the major cause of death for breast cancer patients. In fact, in patients where solid secondary tumors are identified, the long-term survival rate falls from 90% to around 5%. Despite the progress in the development of targeted therapies, approximately 40% of treated patients relapse and ultimately die of metastatic breast cancer.
Malignant breast tumors can invade and damage nearby tissues and organs, and can also metastasize, entering the bloodstream or lymphatic system. When breast cancer cells metastasize outside the breast, they are often found in the lymph nodes under the arm (i.e., the axillary lymph nodes). If the cancer has reached these nodes, it means that cancer cells may have spread to other lymph nodes or other organs, such as bones, liver, brain or lungs. Breast cancer metastasis of various organs also occurs without previous spreading to lymph nodes. Intensive research in recent years has focused on early detection, treatment, and prevention of metastatic breast cancer.
As noted in U.S. Patent Application Publ. No. 20100113297 (specifically incorporated herein in its entirety by express reference thereto), the rational development of preventive, diagnostic and therapeutic strategies for women at risk for breast cancer would be significantly enhanced by a better understanding of the molecular map of the tumorigenic process, but, “relatively little is known of the molecular events that mediate the transition of normal breast cells to the various stages of breast cancer progression. Similarly, little is known of the molecular events that mediate the transition of cells from one stage of breast cancer to another, and finally to metastasis.”
The treatment of brain metastases in breast cancer remains challenging. Whole-brain radiation therapy (WBRT) for palliation as a backbone in the management of brain metastasis yields an extended median survival time of only about 3 to 6 months, and often severely impacts the quality of life in those final months. Surgical resection of the tumor prolongs survival only in patients having a single lesion, and a well-controlled systemic disease. The use of stereotactic radiosurgery in combination with WBRT has provided better local control; nevertheless, minimal overall survival benefit is often seen. For drug treatment options, corticosteroids are used to reduce peritumoral edema, and to provide symptomatic relief. The use of systemic chemotherapy and hormonal therapy has been generally disappointing, which is often attributed to the impermeability of the blood-brain barrier (BBB) and the blood-tumor barrier (BTB), and efflux of the drug by P-glycoprotein (Pgp) activity. Unfortunately, there are no approved or widely accepted treatment methods for brain metastases of breast cancer other than the limited aforementioned strategies. What is lacking in the art are methods for accurately predicting the likelihood of brain metastasis of breast cancer, and methods for identifying and/or repositioning known or novel therapeutics for use in the treatment of metastatic breast cancer.